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Lipid Management for the Prevention of Atherosclerotic Cardiovascular Disease

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Lipid Management for the Prevention of Atherosclerotic Cardiovascular Disease The new england journal of medicine Review Article John A. Jarcho, M.D., Editor Lipid Management for the Prevention of Atherosclerotic Cardiovascular Disease Erin D. Michos, M.D., M.H.S., John W. McEvoy, M.B., B.Ch., M.H.S., and Roger S. Blumenthal, M.D.​​ n 1961, the investigators involved in the Framingham Heart Study From the Ciccarone Center for the Pre- identified serum cholesterol as one of the “factors of risk” for coronary heart vention of Cardiovascular Disease, Johns 1 Hopkins University School of Medicine, disease. Since then, numerous epidemiologic studies and randomized clinical Baltimore (E.D.M., R.S.B), and the Na- I tional Institute for Prevention and Cardio- trials have established that an elevated level of low-density lipoprotein (LDL) choles- terol is a major contributor to atherosclerotic cardiovascular disease.2,3 As a con- vascular Health, National University of Ireland, Galway (J.W.M.). Address reprint sequence, the management of serum cholesterol levels has become a central objec- requests to Dr. Michos at the Division of tive in the effort to prevent cardiovascular events. The currently used therapies Cardiology, Johns Hopkins School of with demonstrated efficacy (see Table S1 in the Supplementary Appendix, avail- Medicine, Blalock 524-B, 600 N. Wolfe St., Baltimore, MD 21287, or at edonnell@ able with the full text of this article at NEJM.org) predominantly target the apolipo- jhmi . edu. protein B–associated lipoproteins reflected in levels of LDL cholesterol, non–high- N Engl J Med 2019;381:1557-67. density lipoprotein cholesterol (non-HDL cholesterol), and triglycerides (Fig. 1). DOI: 10.1056/NEJMra1806939 The most recent guidelines for cholesterol management put forward by the Copyright © 2019 Massachusetts Medical Society. American College of Cardiology–American Heart Association (ACC–AHA) were published in 2018 (Fig. 2).4 In 2019, the ACC–AHA published guidelines for the primary prevention of cardiovascular disease, carrying forward recommendations for risk estimation and lipid management from the 2018 guidelines on cholesterol management.5 Informed by these new guidelines and other recent advances in treatment, this review is intended to summarize current methods of managing serum lipid levels for the prevention of atherosclerotic cardiovascular disease. Lifestyle Management The foundation for managing serum cholesterol is the facilitation of a healthy lifestyle (which includes diet) across a person’s life span.5,6 Even persons whose genetic profile puts them at increased risk for coronary heart disease can reduce their risk by up to 50% through changes in lifestyle.7 Maintenance of a normal weight and blood sugar level, reduction in the intake of simple sugars and refined carbohydrates, and increases in physical activity all improve lipid levels and pro- vide other healthful benefits4,8,9 and should be undertaken regardless of whether pharmacotherapy is also recommended. Dietary and other changes in lifestyle recommended for the management of lipid levels are discussed further in the Supplementary Appendix. LDL Cholesterol Level and Risk The direct relationship between LDL cholesterol level and the risk of atheroscle- rotic cardiovascular disease10 has led to the simple recommendation that “lower is better.” However, measurement of LDL cholesterol levels alone is not sufficient to assess cardiovascular risk. Approximately 40% of persons with coronary heart disease have a total cholesterol level of less than 200 mg per deciliter (5.2 mmol n engl j med 381;16 nejm.org October 17, 2019 1557 The New England Journal of Medicine Downloaded from nejm.org by JESUS DE JUAN MONTIEL on October 17, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Exogenous Pathway Endogenous Pathway Dietary fat Free cholesterol Triglycerides Cholesterol Cholesteryl ester Phospholipids Phytosterols Fatty acids Squalene Degradation Stomach and LIVER Duodenum Mevalonate ApoB100 HMG CoA reductase Gastric and ABCA1 pancreatic lipases ABCG5/G8 Statins hydrolyze lipid Bile acids HMG-CoA esters Phospholipids Cholesterol VLDL formation Acetyl-CoA Bempedoic Bile acids NPC1L1 acid PCSK9 LDLR Phospholipids Pyruvate Cholesterol PCSK9 inhibitor HDL Glucose formation Biliary micelle formation Ezetimibe ApoER VLDL LDL Cholesteryl ester transfer protein Circulation Intestine Portal vein Ezetimibe Bile acid sequestrants CD36 NPC1L1 IBAT LDL ARTERIAL WALL ApoB 48 Bile acids LDL formed Chylomicron from VLDL formation remnants Foam cell VLDL PROXIMAL ILEAL ENTEROCYTE ENTEROCYTE Atherogenesis Chylomicron and VLDL remnants LPL Chylomicron and VLDL Intestinal Hydrolysis LPL lymphatic lacteal Hydrolysis (to thoracic duct) Chylomicron Chylomicron remnants Chylomicron and VLDL remnants Circulation Fatty acids Muscle internalized for use in (Energy use) muscles or converted into triglycerides for storage Apidose tissue (Energy storage) 1558 n engl j med 381;16 nejm.org October 17, 2019 The New England Journal of Medicine Downloaded from nejm.org by JESUS DE JUAN MONTIEL on October 17, 2019. For personal use only. No other uses without permission. Copyright © 2019 Massachusetts Medical Society. All rights reserved. Lipid Management to Prevent Atherosclerotic Cardiovascular Disease 11 Figure 1 (facing page). Lipid Metabolism and Targets for Pharmacotherapy. per liter). Conversely, many persons with a The gastric lipid pool contains ingested free cholesterol, cholesterol esters, moderate elevation in LDL cholesterol level never phytosterols, triglycerides, phospholipids, and fatty acids (see exogenous have a clinical cardiovascular event. In the 2013 pathway). Gastric and pancreatic lipases hydrolyze lipid esters. Bile acids, ACC–AHA guidelines on the management of phospholipids, and cholesterol are secreted by hepatocytes by means of cholesterol,12 there was a movement away from specific transporters (ABCG5, ABCG8, and ABCB11) into the biliary system. targeting specific LDL cholesterol values and Conversely, the Niemann–Pick C1-like 1 (NPC1L1) protein facilitates the toward a focus on treatment of persons at the transfer of cholesterol from bile back into hepatocytes. Ezetimibe blocks biliary NPC1L1. Bile acids and lipids generate complex biliary micelles that greatest absolute risk of cardiovascular disease transport the lipids to intestinal microvilli absorption sites. NPC1L1 facili- with high-intensity statins.12 As cardiovascular tates the entry of cholesterol into enterocytes, a step that is also blocked risk increases, so does the absolute benefit of by ezetimibe. Fatty-acid transport proteins such as CD36 regulate the ab- treatment with therapies proved to lower LDL sorption of de-esterified fatty acids and monoacylglycerols. Once freed cholesterol levels.13,14 Since publication of the from micelles, bile acids are reabsorbed by the ileal bile-acid transporter (IBAT) and released into the portal circulation for return to the liver. Bile-acid 2013 guidelines, additional findings from ran- 15,16 sequestrants block the reabsorption of bile acids in the ileum. Cholesterol domized clinical trials have provided further and triglycerides are assembled into chylomicrons through a synthesis path- support for the concept that the magnitude of way that relies on microsomal triglyceride transfer protein and apolipopro- event reduction is proportional to the degree to tein B48. Chylomicrons are secreted into the intestinal lymphatic system which LDL cholesterol is lowered.10,13 Thus, both before entering the circulation at the thoracic duct. Triglyceride-rich lipo- proteins, such as chylomicrons and very-low-density lipoproteins (VLDL), the absolute risk and the magnitude of the re- undergo lipolysis (hydrolysis of core triglycerides and surface phospholip- duction in LDL cholesterol level achieved are ids) through the interaction of apolipoprotein cholesterol-II and lipoprotein important. The 2018 cholesterol guidelines bring lipase (LPL) in the muscle and adipocyte vascular beds, allowing fatty acids back recommendations for specific percentage to be internalized and used in muscles as an energy source or synthesized reductions in LDL cholesterol levels as well as into triglycerides for energy storage in adipocytes. The action of LPL on chylomicrons reduces their fatty-acid content and results in the production of the use of LDL cholesterol thresholds for the ad- chylomicron remnants; similarly, VLDLs are converted into VLDL remnants dition of nonstatin therapy to statins in patients (intermediate density lipoproteins [IDLs]). at high risk for atherosclerotic cardiovascular Hepatic synthesis of cholesterol (see endogenous pathway) begins with disease (Fig. 2).4 the conversion of glucose to pyruvate by means of a synthesis pathway that relies on the substrate acetyl coenzyme A (CoA), which is created during the Krebs cycle. β-hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase is the Shared Decision Making rate-limiting enzyme in this pathway, forming squalene and several sterol intermediates and ultimately cholesterol. Statins inhibit HMG-CoA reduc- One critical feature of both the 2013 and 2018 tase. Bempedoic acid is a prodrug that is converted by the very-long-chain cholesterol guidelines is the recommendation acyl-CoA synthetase-1 (an enzyme present in hepatocytes but not myocytes) that clinicians conduct a general discussion of into an active metabolite that reduces the production of acetyl CoA in hepa- cardiovascular risk with
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